Project Summary Metabolic disease and stress-related disorders have long been known to exhibit significant comorbidity. Given the clinical relevance of both obesity and stress-related disorders, understanding the mechanisms and identifying specific neural substrates that mediate the interaction between energy balance and stress is essential to develop more effective treatments for these diseases. The overlap in neural circuitry governing energy balance and stress-related physiological and behavioral responses plays a significant role in mediating the high degree of comorbidity between obesity and stress. Efforts to understand the relationship between energy balance and stress have primarily centered on the activation of common downstream neuroendocrine circuitry (e.g. hypothalamic pituitary adrenal [HPA] axis) however, much less is known about the common upstream neurobiological substrates. Serotonin (5-HT) and the central glucagon-like peptide-1 (GLP-1) system, both of which are involved in the control of stress and energy balance, have been shown to interact at the cellular/molecular level. The mechanism, as well as the physiological/behavioral effects of this interaction remain to be determined and will be the focus of this proposal. Preliminary data show that the food intake suppressive effects of hindbrain 5-HT is dependent on central GLP-1 signaling and that this effect is, at least in part, mediated through the activation of the 5-HT2C and 5-HT3 receptors. These data indicate that the interaction between 5-HT and central GLP-1 is relevant for the physiological effects on food intake regulation. This application will therefore test the hypothesis that 5-HT acts as an endogenous modulator of the central GLP-1 system and that satiation signaling and stress-induced hypophagia are both controlled by 5-HT mediated activation of the GLP-1 system. The proposed aims will (Aim 1) assess the presence of 5-HTRs on PPG neurons and explore the behavioral mechanism(s) through which 5-HT activation of the central GLP-1 system suppresses food intake, (Aim 2) determine the physiological relevance of the central GLP-1 system in mediating the intake suppression induced by feeding, stress, and 5-HT, and (Aim 3) explore potential central sources of 5-HT input onto NTS PPG neurons, as well as downstream nuclei to which these 5-HT-activated PPG neurons project. Together, the proposed aims will help broaden our understanding of the interaction between 5-HT and GLP-1 and highlight its importance in the regulation of energy balance.